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Sorting Through the Tangles:
Alzheimer’s Disease
SHP – Neurobiology of Development and Disease
Alzheimer’s Disease
• Early symptoms feature memory loss (amnesia)
beginning with minor forgetfulness which
intensifies with progression of the disease.
• Deficits over time spread to processes including:
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Coordinated motor function (apraxia)
Language (aphasia)
Recognition of familiar people (agnosia)
Variety of loss in prefrontal lobe processes
Discovery:
• Symptoms of the disease were initially described by Emil
Kraepelin.
• In 1907 Alois Alzheimer (Kraepelin’s student)
characterizes the clinical case of a middle-aged woman
suffering from memory loss and cognitive defects.
• She was unreasonably suspicious of her husband, memory
declined, hid objects in her home, and felt as if someone
were trying to kill her.
• She was interned in a psychiatric hospital where she died 5
years later.
• Autopsy of patient reveals classic AD neuropathology:
neurofibrillary tangles and senile plaques in the neocortex
and hippocampus.
Epidemiology:
• Most common cause of dementia in the
elderly.
• Effects 7% of people older than 65 and
~40% above 80.
• As baby boomer generation become seniors,
the incident of this disease is expected to
triple
Progression of the AD
The Ensuing Damage
• Damage seems to be selective to
certain parts of the brain and
some cell types are more
vulnerable than others.
• Most obvious ultrastructural
changes are a shrinking of
hippocampus, expansion of the
ventricles and sulcus
enlargement (or gyrus
shrinkage).
Cellular and
Local Death
Areas most susceptible
• Neocortex and enterrhinal cortex are the
most severely damaged – primary a loss
of excitatory large glutaminergic
pyramidal neurons and interneurons.
• Hippocampus – pyramidal neurons are
more vulnerable and damage focuses on
CA1 and CA2 region.
• Cholinergic neurons in nucleus basalis,
medial spetal nucleus, and diagonal
band of Broca are destroyed.
Neurofibrillary Tangles
http://www.alzheimers.org/rmedia/graphicslowres.htm
5 Principle Genetic Risks:
• Mutation in the amyloid precursor protein (App)
(chromosome 21)
• Mutation sin the presenilin 1 gene (chromosome
14)
• Mutation in the presenilin 2 gene (chromosome 1)
• Alleles for the ApoE gene (chromosome 19)
• Potential mutation or polymorphism in gene on
chromosome 12 that encodes alpha-2
macroglobulin
Amyloid Precursor Protein (APP)
• Transmembrane glycoprotein that is 695, 751, or 770 amino acids long
• Localized to dendrites, soma, and axons of neurons (neuronal APP is
thought to be the source of most of the amyloid-beta.
• It is internalized and processed by a number of proteases, releasing a
number of species of peptide fragments 1-40, 1-42, and 1-43.
• A-beta 1-41/43 have been shown to be more likely to oligomerize into
amyloid plaques.
• 1-42 fragment appears to be neurotoxic for unknown reasons
Amyloid Theory
• Amyloid: histological name
for fibrillar peptides arranged
as beta-sheets in aggregates
that are refractive in polarlized
light and Congo Red stain
• Extracellular APP fragments
can associate into plaques
around neurons and cause
degeneration and death in
surrounding cells.
APP undergoes extensive
Proteolytic Processing
Primary cleavage by
Beta-secretase appears to
Be required for amyloidforming peptide
fragments
APP Alleles
•
Various missense
mutations lie in the APP
gene in different
populations and are
inherited
• ~10% of individuals with
these mutations develop
clinical AD symptoms by
age 50
• Inherited in autosomal
dominant manner mutation
in the 717 position increase
1-42 and 1-43 levels and is
especially toxic and
amyloid forming
Human APP
expressed in mice
• Expression of these human
mutants in mice replicate the
neuropathological features,
degeneration and death.
• Astrogliosis can be seen (in d)
by GFAP staining
• Amyloid formation is
highlighted by thioflavin S
(Congo Red)
• These mice also have impaired
memory and learning
APP-mut
Wt
AD Genes in Development
• Presenilin is homologous to a C
elegans gene called sel-1 that is
required for cell lineage
decisions in neural development
• The physiological role of APP is
still unclear.
• Presenilins have been shown to
be required for Notch signaling
in Drosophila for transmembrane
proteolytic cleavage
Notch Pathway
• Notch is a transmembrane
receptor that binds a
transmembrane ligand
(Delta/Serrate)
• This binding causes
proteolytic cleavage of
Notch, which diffuses to
the nucleus and regulates a
cell transcription program
that blocks neural fate.
APP Destroys Synaptic Integrity
• PSD95 postsynaptic
adaptor protein is
dramatically diminished in
APP mutant neurons
• Blockade of APP cleavage
by gamma-secretase
inhibitor DAPT blocks this
effect.
Mutant APP Blocks Integration
of Glutamate Receptors
• In neurons expressing
the mutant form of
APP, the glutamate
receptor (GluR1)
cannot make it to the
cell membrane
• Inhibition of gammasecretase (DAPT)
blocks this effect
Treatment
• Clinical treatment for AD only focus on the
symptoms but can do nothing to the etiology of
the disease.
• The cholinergic signaling defects can be overcome
by acetylcholinesterase inhibitors
• Glutamate excitotoxicity seem to be involved to
come extent so treatment with NMDA antagonists
are often used.
• The latest approach as been developing vaccines
and immunotreatments to target the most likely
cause of the degeneration: APP amyloid
fragments.
Three Approaches of
Immunotherapy
Mechanism of Antibody function
• Small percentage of
antibodies can cross the
blood-brain barrer and bind
to extracellular A-beta
monomers, oligomers, and
amyloid plaques
• These antibodies then
recruit immune cells to
clear the “wreckage” of
damaged tissue and
proteins themselves or
block protein-protein
interaction directly.
Synopsis of Immunotherapies for AD